Abstract Interleukin-5 (IL-5) is a cytokine that stimulates proliferation and differentiation of B cells including CD5-positive B (B-1) cells and eosinophils. IL-5 signals can be transduced through IL-5 receptor (IL-5R) that is composed of α and βc chains. The IL-5Rα specifically binds IL-5 and the βc chain forms the high-affinity receptor with IL-5Rα and is indispensable for IL-5 signal transduction, although it does not bind IL-5 by itself. The βc chain is shared among receptors for IL-5, IL-3, and GM-CSF. IL-5 induces rapid tyrosine phosphorylations of the βc chain, phosphatidylinositol-3 (P1-3) kinase, Shc, Vav and HS1 and activates Bruton′s tyrosine kinase (Btk) and JAK2 protein tyrosine kinases. Both the cytoplasmic domain of the βc chain and the membrane-proximal proline-rich sequence of the cytoplasmic domain of IL5Rα are essential for the IL-5-induced proliferative response, expression of nuclear proto-oncogenes, and tyrosine phosphorylation of cellular proteins. The dimerization of the cytoplasmic domain of the βc chain appears to activate the IL-5R complex for signaling. B cells from X-linked immunodeficient (XID) mice show decreased expression of IL-5R and impaired IL-5 responsiveness, while their eosinophils respond normally. This B-cell-specific defect of IL-5 responsiveness cannot be rescued by the enforcement of IL-5Rα expression on B cells. These results indicate that XID mice have B-cell-specific defects in IL-5 signaling. The xid gene defect results in failure of B cells to become phenotypically and functionally diverse. Since a single conserved residue within the amino-terminal unique region of Btk has been shown to be mutated in XID mice, this Btk defect in XID mice may be involved in the defective IL-5 signaling.